Cutaneous squamous cell carcinomas (SCCs) emerge as a serious sequela in selected forms of epidermolysis bullosa (EB), carrying elevated risks of morbidity and mortality along with considerable gaps in effective management strategies. Elevated endogenous mutagenesis coupled with a desmoplastic stromal reaction is implicated in disease development. Individuals with dystrophic EB (DEB) and Kindler EB (KEB) are most at risk of SCC formation. A parallel high-risk cohort includes immunosuppressed (IS) patients, notably organ transplant recipients. This work explores potential dysregulation of immune checkpoint proteins and suppressive enzymes in EB-related SCCs to evade host immunity. Expression profiles are contrasted with those detected in SCCs from IS patients—who commonly manifest aggressive lesions—as well as sporadic tumors in immunocompetent (IC) subjects. Immunohistochemistry coupled with semi-quantitative scoring was employed to assess indoleamine 2,3-dioxygenase (IDO), programmed cell death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), T cell immunoglobulin and mucin-domain-containing protein-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), and key inflammatory populations (CD4, CD8, and CD68) in cohorts comprising 30 DEB-SCCs, 22 KEB-SCCs, 106 IS-SCCs, and 100 IC-SCCs. DEB-SCCs exhibited markedly elevated IDO and PD-L1 within carcinoma cells and increased PD-1 in the tumor microenvironment (TME) relative to both IC-SCCs and IS-SCCs. CD4-positive T-cell density per mm² proved significantly diminished in DEB-SCCs compared with IC-SCCs. KEB-SCCs displayed minimal expression of the T-cell exhaustion markers TIM-3 and LAG-3 across all evaluated groups. Collectively, these observations highlight IDO, PD-1, and PD-L1 as upregulated in EB-SCCs and warrant consideration as candidates for combined therapeutic approaches, particularly in DEB-SCC cases.
